End-stage renal disease (ESRD) has a prevalence of about 300,000 people in the U.S. at an annual cost of nearly 15 billion dollars. This is a particularly important concern in S.C., which is second only to the District of Columbia in the incidence of ESRD. Diverse diseases ranging from hypertension to systemic lupus erythematosus can affect the kidney, eventually leading to renal failure. Although those diseases vary in their extrarenal manifestations and in the specific factors that initiate renal damage, a key target for all of these diseases is the glomerulus, particularly the mesangial cell. The multifunctional mesangial cell can only respond to stress in a limited number of ways: proliferation, contraction, inflammation and changes in the glomerular basement membrane that lead to irreversible fibrosis. Unfortunately, our understanding of the mechanisms leading to mesangial cell activation in renal disease is still rudimentary. It is known that there are two phases to chronic glomerular disease. The first phase is probably initiated by increased levels of growth factors and/or toxins and is associated with proliferation of glomerular cells. This abnormal proliferative activity results in cellular expansion in the renal mesangium. The second phase shows decreased proliferation associated with deranged metabolism of extracellular matrix (ECM), leading to fibrosclerosis. Sclerosis is a result of disordered metabolism of ECM such that the balance between production and degradation is shifted in favor of production, and the composition of the ECM is also altered. This is a cardinal feature of glomerulosclerosis regardless of the initiating disease. Understanding the pathways that regulate both proliferation and fibrogenesis may be the key to developing strategies to halt the progression of chronic renal diseases. Ideally, those strategies would be applicable regardless of the initiating factor or specific disease. We hypothesize that a key element that regulates both proliferative and fibrotic signals in mesangial cells is a multicomponent enzyme called NAD(P)H oxidase, which generates reactive oxygen species (ROS). Our proposed studies address an important gap in our knowledge of signals that initiate and propagate chronic renal diseases. In order to test the hypothesis, we propose two specific aims. Number 1. To establish a central role for mesangial cell NAD(P)H oxidase in conveying proliferative and fibrotic signals in cultured mesangial cell models. To identify the target of NAD(P)H oxidase in the pathway of ERK activation vis-a-vis the known components of the ERK activation pathway. Number 2. To establish a role for ROS generated by NAD(P)H oxidase in an animal model of proliferative and fibrotic renal disease.